The goal of this research is to develop a new class of safe and effective therapeutics that alter Alzheimer's disease (AD) progression by targeting activated glia and the resultant neuroinflammation. The hypothesis being tested is that our orally bioavailable, brain-penetrant, novel anti-neuroinflammatory lead compound that shows efficacy in animal models of AD-relevant pathophysiology can be developed further into a set of drug candidates such that a best clinical candidate can be taken to an IND filing by an identified industrial partner at the completion of the proposed investigations. Our novel class of orally bioavailable, CNSselective, small molecule compounds reduce the up-regulated production of the pro-inflammatory cytokines IL-1? and TNF? by activated glia, with a resultant neuroprotection and suppression of AD-relevant pathophysiology progression. The discovery approach is novel and addresses at the front end several of the root causes for late stage drug development failure. The discovery chemistry uses a fragment-based approach in which a focused expansion of an inactive fragment is done based on a rational hierarchal process that is interdisciplinary, employing decision filters assisted by computational biology, synthetic feasibility, and biological screens. Starting one year ago, we applied this approach to the expansion of the inactive 3-amino-6-phenylpyridazine scaffold and developed a novel set of lead compounds with the appropriate molecular properties and function. The lead compound for this proposal is termed MW01-5-188WH. In a mouse model of AD-relevant pathophysiology, daily oral administration of MW01-5-188WH begun three weeks after the start of controlled intracerebroventricular infusion of human A????? suppresses pathophysiology-associated increases in the hippocampus levels of IL-1? and TNF?, resulting in the improvement of synaptic dysfunction, as assayed by biochemical endpoints, and improvement in hippocampal-dependent behavioral deficits. In addition to being orally biovailable, MW01-5-188WH shows good brain uptake and no detectable tissue toxicity at either acute high doses or chronic therapeutic doses. MW01-5-188WH selectively suppresses CMS inflammation versus peripheral inflammation. The proposed studies are for medicinal chemistry optimization of MW01-5-188WH and biological testing of the analogs for retention of efficacy, selectivity, bioavailability, brain uptake and lack of toxicity while improving key molecular properties, such as aqueous solubility, that have been linked to favorable outcomes in translational research and late stage drug development. The optimization strategy utilizes the established and validated platform that led to the development of MW01-5-188WH. This U01 project has highly feasible annual milestones, with the final one being development of a synthetic protocol compatible with GMP synthesis by an FDA compliant contract research organization. [unreadable] [unreadable] [unreadable]